Abstract
Gene transcription can be regulated by remote enhancer regions through chromosome looping either in cis or in trans. Cancer cells are characterized by wholesale changes in long-range gene interactions, but the role that these long-range interactions play in cancer progression and metastasis is not well understood. In this study, we used IGFBP3, a gene involved in breast cancer pathogenesis, as bait in a 4C-seq experiment comparing normal breast cells (HMEC) with two breast cancer cell lines (MCF7, an ER positive cell line, and MDA-MB-231, a triple negative cell line). The IGFBP3 long-range interaction profile was substantially altered in breast cancer. Many interactions seen in normal breast cells are lost and novel interactions appear in cancer lines. We found that in HMEC, the breast carcinoma amplified sequence gene family (BCAS) 1–4 were among the top 10 most significantly enriched regions of interaction with IGFBP3. 3D-FISH analysis indicated that the translocation-prone BCAS genes, which are located on chromosomes 1, 17, and 20, are in close physical proximity with IGFBP3 and each other in normal breast cells. We also found that epidermal growth factor receptor (EGFR), a gene implicated in tumorigenesis, interacts significantly with IGFBP3 and that this interaction may play a role in their regulation. Breakpoint analysis suggests that when an IGFBP3 interacting region undergoes a translocation an additional interaction detectable by 4C is gained. Overall, our data from multiple lines of evidence suggest an important role for long-range chromosomal interactions in the pathogenesis of cancer.
Highlights
It is widely recognized that the spatial organization of the genome and its linear sequence is essential for normal genome function [1]
To better understand the role of Insulin-like growth factor binding protein 3 (IGFBP3) in breast cancer, we analyzed its expression in primary breast cells, the estrogen receptor alpha (ERa) positive breast cancer cell line MCF7, and the triple-negative breast cancer cell line MDA-MB-231
epidermal growth factor receptor (EGFR) Interacts Significantly with IGFBP3 To identify whether changes in IGFBP3 expression and methylation were accompanied by global alteration of its longrange chromatin interactions, we performed multiplex 4C-seq in human mammary epithelial cells (HMEC), MCF7 and MDA-MB-231
Summary
It is widely recognized that the spatial organization of the genome and its linear sequence is essential for normal genome function [1]. Three-dimensional chromatin structure is important in the regulation of transcription [5], and in the control of epigenetic states (including the regulation of imprinted genes) by means of chromosome looping between distant regulatory regions on the same or on different chromosomes [6,7]. We observed a substantial alteration in chromatin structure within human cancers that have lost IGF2 imprinting, resulting in a striking loss of longrange interactions across the IGF2/H19 locus [11]. These studies indicate that a better understanding of intricate 3D chromatin organization is crucial to understanding human diseases, cancer, in which genomic instability and dysregulation are widespread
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